The long-term objective of our research is to define alterations in the extracellular matrix (ECM) interactions that play a role in the development of cancer. Metastasis of epithelial tumors, such as breast carcinomas, occurs when the cells are no longer constrained by the basement membrane that separates them from the underlying stroma. Matrix metalloproteinases (MMPs) are implicated in degradation of the basement membrane during cancer invasion and metastasis. Their activity is controlled, in part, by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). TIMP-3 is the only member of the TIMP family that localizes to the ECM. Based on our studies of TIMP-3 expression in cultured cells and in vivo, we propose the following hypothesis: TIMP-3 is an onco-fetal protein; although it is synthesized in some adult tissues, it is predominantly expressed during embryogenesis and is developmentally regulated. A NMR tertiary structure of a truncated TIMP-2 is available. These coordinates were used to view the truncated TIMP-2 structure using MidasPlus. TIMP-3 is over 60% homologous to TIMP-2. In looking at the truncated TIMP-2 model, MidasPlus aided us in making projections of TIMP-3's structure. More recently, full TIMP-2 and TIMP-1 structures were solved by X-ray crystallography. We have started to use MidasPlus to compare these structures and improve our projections of TIMP-3. This has given us some insights to possible sites for the inhibitory interactions, cytokine signaling and localization epitopes.